Fabrice Uhel1,2,3,4, Imane Azzaoui3,4, Murielle Grégoire3,4, Céline Pangault3,4, Joelle Dulong3,4, Jean-Marc Tadié1,2,3,4, Arnaud Gacouin1,2, Christophe Camus1,2, Luc Cynober5,6, Thierry Fest3,4, Yves Le Tulzo1,2,3,4, Mikael Roussel3,4, Karin Tarte3,4. 1. 1 Centre Hospitalier Universitaire Rennes, Maladies Infectieuses et Réanimation Médicale, Rennes, France. 2. 2 Institut National de la Santé et de la Recherche Médicale, Centre d'Investigation Clinique-1414, and. 3. 3 Unité Mixte de Recherche U917, Institut National de la Santé et de la Recherche Médicale, Université Rennes 1, Etablissement Français du Sang Bretagne, Rennes, France. 4. 4 Centre Hospitalier Universitaire Rennes, Laboratoire Suivi Immunologique des Thérapeutiques Innovantes, Rennes, France. 5. 5 Assistance Publique-Hôpitaux de Paris Hôpital Cochin, Service de Biochimie, and. 6. 6 Département de Nutrition Equipe d'Accueil 4466, Faculté de Pharmacie, Université Paris Descartes, Paris, France.
Abstract
RATIONALE: Sepsis induces a sustained immune dysfunction responsible for poor outcome and nosocomial infections. Myeloid-derived suppressor cells (MDSCs) described in cancer and inflammatory processes may be involved in sepsis-induced immune suppression, but their clinical impact remains poorly defined. OBJECTIVES: To clarify phenotype, suppressive activity, origin, and clinical impact of MDSCs in patients with sepsis. METHODS: Peripheral blood transcriptomic analysis was performed on 29 patients with sepsis and 15 healthy donors. A second cohort of 94 consecutive patients with sepsis, 11 severity-matched intensive care patients, and 67 healthy donors was prospectively enrolled for flow cytometry and functional experiments. MEASUREMENTS AND MAIN RESULTS: Genes involved in MDSC suppressive functions, including S100A12, S100A9, MMP8, and ARG1, were up-regulated in the peripheral blood of patients with sepsis. CD14posHLA-DRlow/neg monocytic (M)-MDSCs were expanded in intensive care unit patients with and without sepsis and CD14negCD15pos low-density granulocytes/granulocytic (G)-MDSCs were more specifically expanded in patients with sepsis (P < 0.001). Plasma levels of MDSC mediators S100A8/A9, S100A12, and arginase 1 were significantly increased. In vitro, CD14pos- and CD15pos-cell depletion increased T-cell proliferation in patients with sepsis. G-MDSCs, made of immature and mature granulocytes expressing high levels of degranulation markers, were specifically responsible for arginase 1 activity. High initial levels of G-MDSCs, arginase 1, and S100A12 but not M-MDSCs were associated with subsequent occurrence of nosocomial infections. CONCLUSIONS: M-MDSCs and G-MDSCs strongly contribute to T-cell dysfunction in patients with sepsis. More specifically, G-MDSCs producing arginase 1 are associated with a higher incidence of nosocomial infections and seem to be major actors of sepsis-induced immune suppression.
RATIONALE: Sepsis induces a sustained immune dysfunction responsible for poor outcome and nosocomial infections. Myeloid-derived suppressor cells (MDSCs) described in cancer and inflammatory processes may be involved in sepsis-induced immune suppression, but their clinical impact remains poorly defined. OBJECTIVES: To clarify phenotype, suppressive activity, origin, and clinical impact of MDSCs in patients with sepsis. METHODS: Peripheral blood transcriptomic analysis was performed on 29 patients with sepsis and 15 healthy donors. A second cohort of 94 consecutive patients with sepsis, 11 severity-matched intensive care patients, and 67 healthy donors was prospectively enrolled for flow cytometry and functional experiments. MEASUREMENTS AND MAIN RESULTS: Genes involved in MDSC suppressive functions, including S100A12, S100A9, MMP8, and ARG1, were up-regulated in the peripheral blood of patients with sepsis. CD14posHLA-DRlow/neg monocytic (M)-MDSCs were expanded in intensive care unit patients with and without sepsis and CD14negCD15pos low-density granulocytes/granulocytic (G)-MDSCs were more specifically expanded in patients with sepsis (P < 0.001). Plasma levels of MDSC mediators S100A8/A9, S100A12, and arginase 1 were significantly increased. In vitro, CD14pos- and CD15pos-cell depletion increased T-cell proliferation in patients with sepsis. G-MDSCs, made of immature and mature granulocytes expressing high levels of degranulation markers, were specifically responsible for arginase 1 activity. High initial levels of G-MDSCs, arginase 1, and S100A12 but not M-MDSCs were associated with subsequent occurrence of nosocomial infections. CONCLUSIONS: M-MDSCs and G-MDSCs strongly contribute to T-cell dysfunction in patients with sepsis. More specifically, G-MDSCs producing arginase 1 are associated with a higher incidence of nosocomial infections and seem to be major actors of sepsis-induced immune suppression.
Authors: Yale Jiang; Brian R Rosborough; Jie Chen; Sudipta Das; Georgios D Kitsios; Bryan J McVerry; Rama K Mallampalli; Janet S Lee; Anuradha Ray; Wei Chen; Prabir Ray Journal: JCI Insight Date: 2020-07-09
Authors: Philip A Efron; Alicia M Mohr; Azra Bihorac; Hiroyuki Horiguchi; McKenzie K Hollen; Mark S Segal; Henry V Baker; Christiaan Leeuwenburgh; Lyle L Moldawer; Frederick A Moore; Scott C Brakenridge Journal: Surgery Date: 2018-05-26 Impact factor: 3.982
Authors: Scott J Denstaedt; Joanna L Spencer-Segal; Michael W Newstead; Klaudia Laborc; Anne P Zhao; Alexander Hjelmaas; Xianying Zeng; Huda Akil; Theodore J Standiford; Benjamin H Singer Journal: J Immunol Date: 2018-03-21 Impact factor: 5.422